The goal of this project is to characterize the role of the neuropeptides NPY and PACAP, and their associated signal transduction pathways. Recently, the discovery of stem cells in the retina and the rostral migratory stream has suggested that postnatal neurogenesis could be an important mechanism for repopulating certain neuronal lineages. Knowledge of how neuronal precursors proliferate in the postnatal brain is crucial to the application of stem cell therapy in the future. The olfactory system is an ideal model in which to study postnatal neurogenesis, due to the architecture, life cycle, in vitro model systems, and ongoing neurogenesis in this system. Our data demonstrate that NPY and PACAP have profound neuroproliferative effects on olfactory neurons. We hypothesize that NPY and PACAP signal the proliferation of olfactory neuronal precursors through separate transduction cascades that may interact. Aim I: determine the distribution of NPY receptors in the olfactory epithelium to demonstrate that NPY receptors are correctly positioned to mediate proliferation in precursor populations. We will use RT-PCR, in situ hybridization, and immunohistochemistry to address these issues. Aim II: establish a proliferative role for NPY in vivo using mice with targeted gene deletion of NPY gene. We will use BrdU labeling and TUNEL staining to determine the effect of the lack of NPY on proliferation and cell death, respectively. Aim III: characterize NPY signaling cascades using our established in vitro preparation of primary cultures of olfactory receptor neurons (ORNs). These experiments will provide insight into the specific roles of NPY and its possible interactions with PACAP cascades on the mechanisms of ORN development.